Role of angiotensin II type 2 receptors in reduced microvascular function in women with a history of preeclampsia

Kelsey S Schwartz

doi:10.25820/etd.007604

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Dissertation

Role of angiotensin II type 2 receptors in reduced microvascular function in women with a history of preeclampsia

Kelsey S Schwartz

University of Iowa

Doctor of Philosophy (PhD), University of Iowa

Summer 2024

DOI: 10.25820/etd.007604

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Abstract

Otherwise healthy women with a history of preeclampsia (hxPE) have a ≥4-fold risk of cardiovascular disease (CVD) morbidity and mortality and develop CVD at a younger age than women who had an uncomplicated pregnancy. This risk is evident despite the remission of clinical preeclampsia symptoms following delivery. Although the lifetime CVD risk following a preeclamptic pregnancy is apparent, the mechanisms underlying this association remain unclear, and there are no approved therapies to prevent disease progression in these high-risk women. Given that CVD is the leading cause of death among women worldwide, studies examining the mechanistic underpinnings of the increased CVD risk associated with preeclampsia are needed to reduce or mitigate chronic disease development in women with a hxPE. Although there is an upregulation of the renin-angiotensin-aldosterone system (RAAS) during healthy pregnancy, pregnant women demonstrate enhanced endothelium-mediated dilation in the maternal vascular beds through a downregulation of vasoconstrictive angiotensin (ang) II type 1 receptors (AT1R) and an upregulation of vasodilatory ang II type 2 receptors (AT2R). In contrast, women with preeclampsia display increased sensitivity to ang II-mediated constriction. Despite a restoration of circulating RAAS components after pregnancy, ang II hypersensitivity persists postpartum following preeclampsia. Notably, women with a hxPE demonstrate attenuated vascular endothelium- and nitric oxide (NO)-dependent dilation, secondary to exaggerated AT1R-mediated constriction, in the years following preeclampsia but before the onset of overt CVD. Rodent models suggest that a downregulation of the counterregulatory AT2R occurs during a preeclamptic pregnancy; however, it is unknown if this persists postpartum. Activation of the counterregulatory RAAS via angiotensin 1-7 can restore endothelial microvascular function in women after preeclampsia, suggesting that the counterregulatory RAAS may be a viable target to improve microvascular function in women with a hxPE. However, to date, no human studies have investigated AT2R agonism in vivo as a counterbalance to heightened ang II-mediated constriction, or to improve endothelium- and NO-dependent dilation in women after preeclampsia. Within this dissertation, the cutaneous circulation was utilized as an easily accessible and representative vascular bed to examine mechanisms of global microvascular function. Although AT2R is a known counterbalance to AT1R-mediated responses, no human studies have examined the functional role of AT2R in vivo in humans. Therefore, the purpose of this series of studies was to examine the functional role of AT2R in vascular function in vivo in humans. Therefore, the first aim sought to establish the feasibility of our approach to examine AT2R-mediated microvascular responses, and to determine if there were sex differences in these responses, in young, healthy adults. Specifically, sex differences in AT2R-mediated dilation and the balance of AT1R and AT2R-mediated responses were assessed in healthy premenopausal women and age-matched men. The results demonstrated that young women have greater AT2R-mediated dilation compared with men and that AT2R-mediated dilation is masked by tonic AT1R activation in young men but not women. These results suggest that enhanced AT2R sensitivity contributes to a pro-dilatory phenotype and favorable CVD risk profile in healthy premenopausal women that is attenuated in age-matched men. Aim 2 utilized the results from aim 1 to examine how alterations in AT1R- and AT2R-mediated responses contribute to an increased vasoconstrictor sensitivity to ang II in otherwise women with a hxPE. We found that AT2R plays a functional role in postpartum vascular function after a healthy pregnancy, in agreement with findings in young healthy women from aim 1. However, AT2R-mediated dilation was attenuated in women with a hxPE. Local inhibition of AT1R improved AT2R-mediated dilation in women with a hxPE, demonstrating that overactivation of AT1R masks AT2R-mediated dilation in women with a hxPE. Further, exaggerated microvascular constriction to ang II in women with a hxPE was found to be mediated, in part, by reductions in AT2R-mediated responses. The results of this study demonstrate that reductions in the vasodilatory AT2R contribute to an increased vasoconstrictor sensitivity to ang II in women with a hxPE by shifting the RAAS balance to favor AT1R-mediated responses. Given that AT2R-mediated responses are attenuated and contribute to overactivation of the constrictor RAAS in women with a hxPE, the third aim examined the role of AT2R in endothelial dysfunction after preeclampsia, and evaluated the potential of activating AT2R to restore balance of the RAAS axes and improve endothelial function. The results of this study found that attenuations in AT2R-mediated dilation are mediated, in part, by reductions in nitric oxide (NO)-dependent mechanisms. Additionally, ex vivo analysis of biopsied endothelial cells found that AT2R protein expression is lower in cells from women with a hxPE compared with hxHC. Lastly, reductions in endothelium- and NO-dependent dilation in women with a hxPE could be improved following local activation of AT2R, suggesting AT2R may be a mechanism-specific target to reduce CVD risk after preeclampsia. In conclusion, the data from this series of studies collectively demonstrate that 1) the AT2R has a functional role in the microvasculature of humans, 2) this role is attenuated following a pregnancy complicated by preeclampsia and contributes to exaggerated ang II-mediated vasoconstriction, and 3) AT2R activation may be a feasible, mechanism-specific therapeutic target to improve microvascular function before the onset of overt cardiovascular disease in women with a history of preeclampsia.

Cardiovascular Disease

Angiotensin II

Endothelial function

Microvascular function

Postpatum health

Preeclampsia

Reading instruction

Details

Title: Subtitle: Role of angiotensin II type 2 receptors in reduced microvascular function in women with a history of preeclampsia
Creators: Kelsey S Schwartz
Contributors: Anna E Stanhewicz (Advisor)
Diana I Jalal (Committee Member)
Gary L Pierce (Committee Member)
Mark K Santillan (Committee Member)
Megan M Wenner (Committee Member)
Resource Type: Dissertation
Degree Awarded: Doctor of Philosophy (PhD), University of Iowa
Degree in: Health and Human Physiology
Date degree season: Summer 2024
Publisher: University of Iowa
DOI: 10.25820/etd.007604
Number of pages: xiii, 117 pages
Language: English
Date submitted: 07/22/2024
Description illustrations: illustrations, tables, graphs
Description bibliographic: Includes bibliographical references (pages 91-117).
Public Abstract (ETD): Preeclampsia is a pregnancy-specific condition where a woman develops high blood pressure and other problems for the first time. Women with a history of preeclampsia (hxPE) appear otherwise healthy following delivery but are over 4 times more likely to develop and die from cardiovascular disease (CVD) compared with women who had a healthy pregnancy. This may be because preeclampsia permanently damages or alters blood vessels. We still do not know what the underlying causes of this damage are, or how to treat the damage after pregnancy. This dissertation addresses this issue by examining if a receptor (angiotensin II type 2 receptor; AT2R) that normally keeps blood vessels healthy is dysfunctional. We used the blood vessels in the skin as a model to study how microvessels function. We study these microvessels because changes in vessel function occur in the smallest vessels before CVD develops. First, we assessed the role of AT2R in vessel function in healthy young adults to make sure we could study it and determine if there were differences between men and women. Next, we examined if AT2R was dysfunctional in healthy women with a hxPE. Lastly, we evaluated if activating AT2R is a good treatment for blood vessel damage in women with a hxPE. We found that AT2R plays an important role in microvessel function in young women, that this role is reduced in women with a hxPE, and that activating AT2R may be a future target to reduce elevated CVD risk in healthy women with a hxPE.
Academic Unit: Health and Human Physiology
Record Identifier: 9984697940602771

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